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Secreted SOCS Proteins as Vectors of Lung Macrophage to Epithelial Cell Crosstalk

分泌的 SOCS 蛋白作为肺巨噬细胞与上皮细胞串扰的载体

基本信息

批准号：
9103201
负责人：
MARC L PETERS-GOLDEN
金额：
$ 56.53万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9103201
关键词：
Acute Alveolar Alveolar Macrophages Anatomy Anti-Inflammatory Agents Anti-inflammatory Antigens Apoptosis Biological Bronchoalveolar Lavage Fluid CISH gene Cell physiology Cells Code Color Communicable Diseases Cytokine Signaling Development Distal Elements Encapsulated Epithelial Cells Extracellular Space Family Foundations Gases Gene Expression Growth Health Homeostasis Human Immune Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Janus kinase Laboratories Lipopolysaccharides Liposomes Lung Lung Inflammation Lung Lavage Fluid Maintenance Membrane Phenotype Physiological Process Property Proteins Pulmonary Inflammation Recombinants Regulation Respiratory physiology Rodent Role STAT protein Scheme Signal Transduction Signaling Protein Surface Testing Therapeutic Therapeutic Effect Tissues Toxin Transcriptional Activation Vesicle Work assault cigarette smoke-induced cigarette smoking cytokine exosome in vitro testing in vivo insight intercellular communication macrophage member mouse model novel novel therapeutic intervention paracrine response restraint uptake vector

项目摘要

DESCRIPTION (provided by applicant): In order to preserve homeostasis and normal gas exchange function, the lung must restrain inflammatory responses to the continual assault posed by infections, antigens, and toxins. Host responses in the distal lung are dictated in large part by the cross-talk between alveolar epithelial cells (AECs), which comprise the alveolar surface, and alveolar macrophages (AMs), its resident immune cells. Little is known about mechanisms by which AMs control inflammatory responses of AECs. We have recently identified a novel form of intercellular communication in which AMs secrete suppressors of cytokine signaling (SOCS) 1 and 3 proteins within membrane-delimited vesicles that can be taken up by AECs to inhibit inflammatory signaling in response to cytokines in vitro and in vivo. AM secretion of SOCS can be "tuned" by certain bioactive molecules, including those elaborated by AECs. Furthermore, cigarette smoking reduces while adenoviral infection increases SOCS levels in lung lavage fluid, indicating that dysregulation of SOCS secretion is associated with the known alterations in inflammatory responses that characterize these conditions. This proposal seeks to better understand the fundamental mechanisms, biological consequences, and therapeutic ramifications of this novel form of AM-AEC cross-talk. Aim 1 will characterize mechanisms regulating the release of two distinct types of vesicles - microparticles and exosomes - and the secretion of SOCS proteins within them, in response to bioactive molecules as well as AEC-derived factors. Aim 2 will determine the mechanisms controlling uptake of these distinct SOCS-containing vesicles in AECs and the effects of transcellular SOCS delivery on cytokine signaling, inflammatory gene expression, proliferation, and apoptosis in the target cells. Aim 3 will characterize the operative mechanisms for and consequences of dysregulated SOCS secretion in mouse models of acute inflammation induced by cigarette smoking and adenoviral infection. In addition, the effects and therapeutic potential of synthetic liposomal vesicles loaded with recombinant SOCS proteins will be tested in vitro and in vivo. These studies will provide new insights into the regulation of lung inflammation and a foundation for a novel therapeutic approach to its control.